Project Summary Persons with type 1 and type 2 diabetes (T1D, T2D) both have increased fracture risk, attributed to specific deficits in the microarchitecture, material properties and strength of diabetic bone. Sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors are a new class of FDA- approved glucose-regulating agents for use in persons with T2D. These drugs (canagliflozin, dapagliflozin and empagliflozin are FDA-approved in the USA and Europe) increase urinary glucose excretion by inhibiting glucose reabsorption in the renal proximal tubule, and thereby improve glycemic control in persons with type 2 diabetes. They are likely to play a prominent role in the future treatment of T2D because of this unique mechanism of action, and because they provide concurrent beneficial reductions in body weight and blood pressure. However, early clinical studies have demonstrated a possible ~30% increase in bone fractures in patients receiving these medications, with fractures occurring as early as 12 weeks of therapy. At present, very little is known about the effects of SGLT2 inhibition on bone mineral homeostasis, bone turnover or bone microarchitecture, or how these drugs specifically impact diabetic bone disease. Therefore, the objective of this proposal is to utilize several relevant rodent models (slc5a2-functional mutants, STZ-induced diabetes, TallyHo) to investigate potential mechanisms contributing to the adverse effects of SGLT2-inhibitor therapy on the skeleton. Furthermore, we will investigate the efficacy of co-therapy with anti-calciuric thiazide diuretic drugs to potentially mitigate the negative effects of SGLT2-inhibitor therapy on the skeleton. Recognizing that a lifelong increased risk for fragility fracture is now an established comorbidity of diabetes, a better understanding of the effects of SGLT2 inhibitors on bone health is both timely and highly relevant to the future of diabetes treatment.